Single-cell transcriptomics uncovers distinct molecular signatures of stem cells in chronic myeloid leukemia

Area of Science:

• Hematology
• Oncology
• Genomics

Background:

• Single-cell transcriptomics can reveal cancer stem cell (SC) heterogeneity and therapy resistance.
• Current methods lack sensitivity for detecting somatic mutations in single cells.
• Understanding intratumoral heterogeneity is crucial for developing effective cancer therapies.

Purpose of the Study:

• To develop a sensitive method for simultaneous mutation detection and whole-transcriptome analysis in single cells.
• To investigate chronic myeloid leukemia stem cell (CML-SC) heterogeneity and therapy resistance.
• To explore cell-extrinsic disruptions in hematopoiesis in CML.

Main Methods:

• Development of a novel technique combining high-sensitivity mutation detection with whole-transcriptome analysis of single cells.
• Application of the technique to analyze over 2,000 SCs from CML patients across the disease course.
• Analysis of nonleukemic SCs from CML patients.

Main Results:

• Identification of CML-SC heterogeneity, including a distinct subgroup persisting during therapy.
• Discovery of a blast-crisis-specific SC population also present in a chronic-phase subclone.
• New insights into cell-extrinsic disruption of hematopoiesis in CML linked to clinical outcomes.

Conclusions:

• The developed single-cell approach enables sensitive mutation detection and transcriptomic analysis.
• This method can identify therapy-resistant SC subpopulations previously undetectable by bulk analysis.
• The findings have broad applicability for identifying resistant SCs in various malignancies.